US20180280429A1 - Application of nitrate in preparation of drug preventing or treating bone metabolic diseases - Google Patents

Application of nitrate in preparation of drug preventing or treating bone metabolic diseases Download PDF

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US20180280429A1
US20180280429A1 US15/764,877 US201515764877A US2018280429A1 US 20180280429 A1 US20180280429 A1 US 20180280429A1 US 201515764877 A US201515764877 A US 201515764877A US 2018280429 A1 US2018280429 A1 US 2018280429A1
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nitrate
bone
application according
metabolic diseases
drug
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Songling Wang
Baoxing Pang
Xingmin Qu
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Capital Medical University
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Capital Medical University
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/02—Ammonia; Compounds thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K33/00—Medicinal preparations containing inorganic active ingredients
    • A61K33/06—Aluminium, calcium or magnesium; Compounds thereof, e.g. clay
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis

Definitions

  • the present application relates to the field of medicine, and more specifically, relates to applications of a nitrate in the preparation of a drug preventing or treating bone metabolic diseases, and the preparation of drugs regulating bodily immune abnormalities and bone marrow mesenchymal stem cell abnormalities.
  • Nitrate is an inorganic substance widely found in nature. Plants can absorb and use nitrate in soil to supply the nitrogen needed in the body. Most of the nitrate in food comes from green vegetables. The traditional view is that dietary nitrates and nitrites have a potential carcinogenic tendency. Then it is recognized that nitrite will only show a carcinogenic effect when it is combined with amines to form nitrite amines under certain conditions and reaches a certain concentration. At present, the exact role of oral nitrate in enhancing blood perfusion and regulating energy metabolism has reached a consensus, which laid a foundation for the application of bone metabolism diseases.
  • Bone metabolic diseases refer to the bone disease that resulted from bone biochemical metabolic disorders due to the innate or acquired factors of the body destroying or interfering with the normal bone metabolism and biochemical status.
  • Abnormal bone density disease one of the common types, refers to a systemic bone disease caused by direct or indirect causes, but it may also be prominently reflected as a bone change in a part of the body, such as the general body decalcification caused by hyperparathyroidism and local bone resorption caused by malignant tumor invasion of bone tissue and so on.
  • Abnormal bone density disease is mainly characterized by a disorder or abnormality in conversion between bone formation and bone resorption, such as the bone formation or bone resorption may be reduced or increased, the bone matrix formation may be absent or increased, the mineralization may also be lacking, insufficient, or excessively deposited.
  • bones may show looseness, softening, hardening, or excessive calcification, or two or more of the above manifestations.
  • osteoporosis is the most common degenerative bone density disease in the elderly, especially in postmenopausal women, with reduction of systemic bone mass, degeneration of bone tissue microstructure, decreased bone strength, increased bone fragility, easy to fracture and body pain as the main lesion characteristics.
  • drugs for the treatment of osteoporosis in the clinic can be divided into drugs for anti-bone resorption, drugs for promoting bone-forming, and drugs promoting bone mineralization and so on.
  • the most commonly used is estrogen replacement therapy (ERT), whose efficacy has been fully affirmed.
  • ERT estrogen replacement therapy
  • ERT a long-term use of estrogen increases the risk of endometrial cancer, breast cancer, and cardiovascular disease.
  • the object of the present application is to provide an application of a nitrate in the preparation of a drug preventing or treating bone metabolic diseases, and a drug containing the nitrate for preventing or treating bone metabolic diseases, aiming at the defects of poor efficacy of the existing therapeutic drugs for bone metabolism diseases.
  • the technical solution adopted by the present application to solve its technical problems is to provide an application of a nitrate in the preparation of a drug preventing or treating bone metabolic diseases. This new use of nitrates is first discovered and provided by the present application.
  • the nitrate is configured for preparing drug preventing or treating osteoporosis.
  • the osteoporosis includes primary osteoporosis such as postmenopausal or senile osteoporosis, and secondary osteoporosis caused by various endocrine disorders or abolishment.
  • the nitrate-produced medicament of the present application is also suitable for diseases in which bone loss is required to be alleviated. Further research shows that nitrate can also regulate bodily immune abnormalities and bone marrow mesenchymal stem cell abnormalities, therefore, the novel use of nitrates in the treatment of osteoporosis discovered for the first time by the present application may be achieved through nitrate regulating immune immunity and bone marrow mesenchymal stem cells.
  • the nitrate is further configured for preparing a drug preventing or treating abnormal bone density diseases.
  • abnormal bone density diseases are caused by that congenital or acquired factors disrupt or interfere with normal bone metabolism and biochemical status, leading to a break in the balance of osteogenesis and osteoclasts, resulting in decreased bone density and even loss of bone mass. It mainly includes osteolytic changes caused by malignant tumors invading bone tissue, loss of bone mass caused by rheumatoid arthritis in violation of cartilage and bone tissue, and loss of bone mass due to thyroid dysfunction and so on.
  • nitrate can significantly relieve the loss of bone mass in rats, therefore, it can also be used to treat these abnormal bone density diseases, especially abnormal bone density caused by bodily immune abnormalities and/or bone marrow mesenchymal stem cell abnormalities.
  • the nitrate is a salt composed of a metal ion and a nitrate ion.
  • the nitrate ion is the main active ingredient of the nitrate. Therefore, any pharmaceutically acceptable salt containing nitrate can be used, preferably a salt composed of a metal ion and a nitrate ion, or ammonium nitrate and the like. Therefore, the nitrate of the present application is selected from a group consisting of one or more of the followings: sodium nitrate, potassium nitrate, and calcium nitrate and ammonium nitrate and so on.
  • the nitrate is provided in the form of a food or an extract that is rich in nitrate.
  • the nitrate in the present application can be provided not only as a compound but also can be provided in a food or an extract. Therefore, the present application also provides new uses for these nitrate-rich foods or extracts for the preparation of a drug preventing or treating bone metabolic diseases accordingly.
  • the concentration of nitrate in vegetables such as spinach, beetroot, white radish, and celery can reach more than 3000 mg/Kg, which is several to ten times as high as that of other common foods.
  • a daily dose of the nitrate is 0.1-0.5 mmol/Kg b.w. More preferably, a daily dose of the nitrate is 0.5 mmol/Kg b.w.
  • a drug preventing or treating bone metabolic diseases is also provided by the present application, which contains nitrate as an active ingredient.
  • a drug preventing or treating abnormal bone density diseases is provided, in which the nitrate is contained as the active ingredient.
  • a drug preventing or treating osteoporosis is provided, in which the nitrate is contained as the active ingredient.
  • the nitrates may also be provided in various forms and dosages as described previously.
  • dosage forms of the drug preventing or treating bone metabolic diseases are tablets, capsules, pills, injections, syrups, oral liquids, granules or patches.
  • the nitrate oral solution can provide a more convenient and effective administration route, and the concentration of the nitrate oral solution is preferably 0.5 mmol/L-2.5 mmol/L, more preferably 2.5 mmol/L.
  • nitrate plays a very good regulatory role in immunologically abnormal diseases in which regulatory T lymphocytes are downregulated and interleukin 17 is upregulated.
  • the present application uses flow cytometry and other technical methods to detect the immune regulation of ovariectomized rats, and finds that nitrate can regulate the immunobiological behavior of ovariectomized rats, such as, relieving the decline of regulating T lymphocytes (Treg) of the ovariectomized rats, relieving the down-regulation of TGF- ⁇ 1 in ovariectomized rats, and relieving the up-regulation of IFN- ⁇ and IL-17.
  • a drug regulating bodily immune abnormalities is also provided by the present application, in which the nitrate is contained as the active ingredient.
  • the nitrates may also be provided in various forms and dosages as described previously.
  • nitrate plays a very good regulatory role in diseases in which bone marrow mesenchymal stem cells have reduced osteogenic potential.
  • the stem cell activity of ovariectomized rats is detected by a technical method such as stem cell culture, and it is found that nitrate can regulate the biological behavior of bone marrow mesenchymal stem cells in ovariectomized rats, for example, significantly reducing the BMMSCs proliferation ability of ovariectomized rats, significantly enhancing its osteogenic differentiation.
  • nitrate is contained as the active ingredient.
  • the nitrates may also be provided in various forms and dosages as described previously.
  • the present application provides new uses of nitrates in the preparation of drugs preventing or treating bone metabolic diseases. Moreover, through a large number of experiments, it has been proved that nitrate can significantly relieve the loss of bone mass in rats. The nitrate has no obvious adverse reactions at the time of bone preservation, and has no significant influence on the body weight of rats. In addition, immune and bone marrow mesenchymal stem cell biological behavior can be controlled in ovariectomized rats. Therefore, it can be prepared as drugs and used for the prevention and/or treatment of osteoporosis and other bone density abnormalities, and bodily immune abnormalities and bone marrow mesenchymal stem cell abnormalities.
  • FIGS. 1A-1F are graphs illustrating the effects of nitrate on bone density and trabecular bone in ovariectomized rats.
  • FIGS. 2A and 2B are graphs illustrating the effects of nitrate on tibia weight and body weight in ovariectomized rats, respectively.
  • FIGS. 3A and 3B are graphs illustrating the difference of nitrate content and nitrite content in serum after drinking water containing nitrate for 3 months, respectively.
  • FIGS. 4A-4D are graphs illustrating the effects of nitrate on immune regulation in ovariectomized rats.
  • FIGS. 5A and 5B are graphs illustrating the results of the nitrate in the improvement of BMMSC defects in ovariectomized rats.
  • the rat tibia was completely separated, and all attached muscles and connective tissue were removed. It was wrapped with wet gauze soaked in physiological saline and stored at ⁇ 20° C. The upper part of the tibia was scanned with a Skyscan 1162 Micro-CT. The scan thickness was 9 ⁇ m. The bone density and trabecular structure were quantitatively analyzed using the attached software.
  • FIGS. 1A-1F are graphs illustrating the effects of nitrate on bone density and trabecular bone in ovariectomized rats.
  • FIG. 1A is a schematic diagram of an experimental process of the nitrate group, in which a 12-week-old SD rat undergoing an ovariectomy operation was given drinking water with sodium nitrate, and after 12 weeks, the animals were sacrificed to collect specimens.
  • FIG. 1A is a schematic diagram of an experimental process of the nitrate group, in which a 12-week-old SD rat undergoing an ovariectomy operation was given drinking water with sodium nitrate, and after 12 weeks, the animals were sacrificed to collect specimens.
  • FIG. 1A is a schematic diagram of an experimental process of the nitrate group, in which a 12-week-old SD rat undergoing an ovariectomy operation was given drinking water with sodium nitrate, and after 12 weeks, the animals were sacrificed to collect specimens.
  • FIG. 1A is a schematic diagram of
  • FIGS. 1C-1F are graphs of bone density (BMD), bone volume fraction (BV/TV), trabecular thickness (Tb.Th), and trabecular number (Tb.N), respectively, of MicroCT quantitative analysis (*P ⁇ 0.05) for each group.
  • BMD bone density
  • BV/TV bone volume fraction
  • Tb.Th trabecular thickness
  • Tb.N trabecular number
  • FIGS. 2A and 2B are graphs illustrating the effects of nitrate on tibia weight and body weight in ovariectomized rats, respectively, (*P ⁇ 0.05). The results show that the drinking water with nitrate can relieve the decrease of tibia weight in ovariectomized rats and has no significant effect on the weight gain of ovariectomized rats.
  • NADH nicotinamide adenine dinucleotide
  • FIGS. 3A and 3B are graphs (*p ⁇ 0.05) illustrating the difference of nitrate content and nitrite content in serum after drinking water containing nitrate for 3 months, respectively. Wherein, the content of nitrate and the content of nitrite in serum were significantly increased by drinking water with nitrate.
  • Anti-Foxp3 is added for incubating on ice for 30 minutes while avoiding light.
  • the serum is diluted for 10 times, and 0.1 ml of which is placed into the 96-well plate of the kit.
  • the standard in the kit is taken and diluted in proportion, and then placed into the 96-well plate and incubated at 37° C./at room temperature for 30 minutes/1 hour according to the instructions.
  • the obtained object is washed with a buffer for 3 times and each time lasts for 3 minutes.
  • FIGS. 4A-4D are graphs illustrating the effects of nitrate on immune regulation in ovariectomized rats (*P ⁇ 0.05).
  • FIG. 4A shows the proportion of regulatory T lymphocytes in peripheral blood CD4 positive cells obtained by flow cytometry analysis of rat peripheral blood from each group. As shown in the Figure, drinking water with nitrate can reduce the decline of the regulatory T lymphocytes (Treg) of the ovariectomized rat.
  • FIGS. 4B-4D show the levels of TGF- ⁇ 1, IFN- ⁇ and IL-17 in the serum of each group. The results show that drinking water with nitrate could alleviate the down-regulation of TGF- ⁇ 1 in ovariectomized rats and alleviate the up-regulation of IFN- ⁇ and IL-17.
  • the skin of the hind limbs was removed.
  • the bone marrow was extracted with a 1 mL syringe to flush out from the stump.
  • Cells were cultured in the ⁇ -MEM complete medium (containing 10% of bovine serum), and subcultured after the cells were clonally grown until 80% of the fusion.
  • 100 ⁇ l of cell suspension was inoculated in the 96-well plate, and the plate was pre-cultured in the incubator for 24 hours (under the condition of 37° C., 5% CO 2 ). Then the plate was incubated in an incubator for 72 hours. 100 ⁇ l of culture medium was added to each well and 10 ⁇ l of CCK-8 solution was added to each hole. After 2 hours, the absorbance at 450 nm was measured with an enzyme labeled instrument.
  • Preparation of osteoinductive medium adding 2 mmol/L glutamine, 100 U/ml penicillin and 100 ⁇ g/ml streptomycin, 10 mM ⁇ -glycerophosphate sodium, and 10 nM Dexamethasone and 50 mg/L vitamin C to 10% fetal bovine serum ⁇ -MEM medium.
  • the 3-4th generation cells were inoculated into a 6-well plate at a concentration of 2 ⁇ 10 3 /cm 2 , and after the cells were grown to 80% confluent, it was replaced with the osteoinductive medium, and the medium was changed every 2 days. The formation of calcium nodules was observed under light microscope. After 2 weeks of induction, alizarin red staining was performed.
  • FIGS. 5A and 5B are graphs illustrating the results of the nitrate in the improvement of BMMSC defects in ovariectomized rats (*P ⁇ 0.05).
  • FIG. 5A shows the OD450 value detected by CCK8 of the third generation cells which are obtained by primary culture of the BMMSC of the rats of each group according to the above method. The results show that the drinking water with nitrate significantly reduced the proliferation of the BMMSCs of ovariectomized rats.
  • FIG. 5B shows the results of alizarin red staining and quantification after 21 days of osteogenesis induction of the BMMSC of rats in each group according to the above method. The results show that the drinking water with nitrate significantly enhanced osteogenic differentiation of the BMMSCs of ovariectomized rats.
  • SPSS 17.0 statistical software was used for statistical analysis. Multiple sets of measurement data were compared using ANOVA analysis. P ⁇ 0.05 was statistically significant.

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PCT/CN2015/098314 WO2017054337A1 (zh) 2015-09-30 2015-12-22 硝酸盐在制备预防或治疗骨代谢疾病的药物中的应用

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10457742B2 (en) 2011-11-04 2019-10-29 Zymeworks Inc. Stable heterodimeric antibody design with mutations in the Fc domain
CN112472714A (zh) * 2020-12-03 2021-03-12 爱希（北京）国际咨询有限公司 一种含硝酸盐的组合物及其应用
US11028182B2 (en) 2015-05-13 2021-06-08 Zymeworks Inc. Antigen-binding constructs targeting HER2

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112472713A (zh) * 2020-12-03 2021-03-12 爱希（北京）国际咨询有限公司 一种防治骨质疏松的组合物及其应用

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4777044A (en) * 1984-06-04 1988-10-11 Bins Jan W Therapeutic preparation having ammonium nitrate as its active substance
US20100092441A1 (en) * 2007-02-26 2010-04-15 Jon Lundberg Use of nitrites and nitrates and compositions containing these

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IT1303672B1 (it) * 1998-07-28 2001-02-23 Nicox Sa Sali nitrati di farmaci attivi nei disordini ossei
CN1120002C (zh) * 1999-10-09 2003-09-03 兰州凯瑞中药科技开发有限公司 硝酸铵在制药、食品和保健品中的应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4777044A (en) * 1984-06-04 1988-10-11 Bins Jan W Therapeutic preparation having ammonium nitrate as its active substance
US20100092441A1 (en) * 2007-02-26 2010-04-15 Jon Lundberg Use of nitrites and nitrates and compositions containing these

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10457742B2 (en) 2011-11-04 2019-10-29 Zymeworks Inc. Stable heterodimeric antibody design with mutations in the Fc domain
US11028182B2 (en) 2015-05-13 2021-06-08 Zymeworks Inc. Antigen-binding constructs targeting HER2
CN112472714A (zh) * 2020-12-03 2021-03-12 爱希（北京）国际咨询有限公司 一种含硝酸盐的组合物及其应用

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